Abstract: End organ failure is the leading health care challenge in the Western World. Improvements in management of acute events and chronic diseases led to a growing patient population suffering from single or multi organ failure. Nearly 6 million Americans suffer from heart failure with about 550,000 new cases diagnosed annually;25 million Americans suffer from chronic obstructive pulmonary disease (COPD) with an estimated 12 million new yearly diagnoses;530,000 Americans suffer from end stage renal disease. Organ transplantation is the only potentially curative therapy available. However, its outcomes are limited by donor organ shortage and the side effects of harsh immunosuppressive treatments. Organ engineering is a theoretical alternative to transplantation. Whole organs could be derived from patient's cells and transplanted similar to donor organs to overcome donor organ shortage, and the need for immunosuppression. Many important milestones have been met towards the goal to build replacement organs. Potential cell candidates have been derived from adult tissue biopsies and differentiated into some of the required cell types such as cardiomyocytes, endothelial cells, pneumocytes, epithelial cells. Culture conditions have been developed to induce the assembly of these cells into functional tissue constructs. However, construction of scaffolds that outline whole organ architecture and enable formation of human size grafts has been a major hurdle. The PI developed and reported a novel technique to isolate whole organ extracellular matrix (ECM) scaffolds by perfusion decellularization. In preliminary studies, these ECM scaffolds supported engraftment of cardiomyocytes and pneumocytes to form viable hearts and lungs that could be transplanted and function in vivo. Other groups have generated lung and liver grafts based on the same technology. We propose to further develop perfusion decellularized scaffolds as a platform for organ engineering by developing conditions suitable for human organs, deriving adult derived cell populations, designing human size bioreactor systems, and developing human organ culture conditions. The proposed research has a high potential clinical impact and may change the field of organ engineering. The project is highly innovative, and requires a creative and flexible multidisciplinary team. The PI as the inventor of the platform technology is an ideal candidate to perform the proposed research. Public Health Relevance: Cardiovascular disease, diabetes, and chronic obstructive pulmonary disease are the three most common chronic diseases in America. Organ transplantation is the only potentially curative therapy available. However, its outcomes are limited by donor organ shortage and the side effects of harsh immunosuppressive treatments. Indeed, there are today 91,000 total patients waiting for a heart, lung, or kidney transplant, with a 2003 median waiting time of 0.6, 2.5, and 3.3 years, respectively. As a result, 5237 Americans died waiting for a suitable donor organ in 2009. Organ engineering based on patient derived cells could offer an alternative to transplantation, potentially alleviating donor organ shortage, and the need for immunosuppression.